Larry E. OvermanRune Risgaard11-2-2013
- Born in 1943 in Chicago, Illinois- Raised in Hammond, Indiana- B.A., Earlham College 1965- Ph.D., University of Wisconsin 1969 with Professor Howard W. Whitlock- NIH postdoctoral fellowship with Professor Ronald Breslow at Columbia University- He joined University of California, Irvine in 1971 where he is Distinguished Professor of Chemistry
Awards/Honours include:ACS Arthur. C. Cope Award (2003)ACS Creative work in Synthetic Organic Chemistry (1995)
2011 - UCI Medal, University of California, Irvine, American Chemical Society, 2010 - Herbert C. Brown Award for Creative Research in Synthetic Methods, 2008 - Tetrahedron Prize for Creativity in Organic Chemistry, 2007 - The Nagoya Medal of Organic Chemistry, 2005 - International Society of Heterocyclic Chemistry Senior Award, 2004 - Ta-shue Chou Lectureship Award, 2003 - American Chemical Society Arthur C. Cope Award, 2002-2003 U.C. Irvine Distinguished Faculty Lectureship Award for Research, 2002 - Yamada Prize 1999 - Japan Society for the Promotion of Science Fellowship, - S. T. Li Prize for Achievements in Science and Technology, - Earlham College Distinguished Faculty Award, 1997 - Centenary Medal, Chemical Society, U.K. 1995 - American Chemical Society Award for Creative Work in Synthetic Organic Chemistry, 1993 - 1994 - Guggenheim Fellowship, 1993 - C.S. Hamilton Award, University of Nebraska 1985 - 1992 - Javits Neuroscience Investigator Award1989 - American Chemical Society Arthur C. Cope Scholar Award - Visiting Miller Research Fellow, U.C. Berkeley 1985 - 1987 - Alexander von Humboldt U.S. Senior Scientist Award, 1976-1981 Camille and Henry Dreyfus Teacher-Scholar Award 1981 - U.C. Irvine School of Physical Sciences Distinguished Teaching Award, 1979 - U.C. Irvine Alumni Association Distinguished Research Award1975-1977 - Alfred P. Sloan Foundation Fellow
Research Interests: Organic, Inorganic, Organometallic and Chemical Biology
- Professor Overman's research interests center on the invention of new reactions and strategies in organic synthesis and the total synthesis of natural products and their congeners.
362 publications:- 128 JACS- 74 JOC- 12 Angew. Chem.- 117 papers with the term "total synthesis"
OH
Larry E. OvermanRune Risgaard11-2-2013
The aza-Cope rearrangement- Mild conditions (100-200 oC below the corresponding Cope rearrangement)- Usually occurs near rt.- Reversible (Driven by aryl conjugation of the product iminium ion)- Charged intermefiate lowers free energy of activation
NHR1
OHR3
NR1
OHR3
R2CHO
R2 NR1
OHR3
R2
[3,3]
N
O
H H
R3
H
R2
Synthesis of cis-fused octahydroindoles and cycloheptapyrrolidines- One carbon ring expansion- Present in alkaloids of the Amaryllidaceae, Aspidosperma, and Strychnos familes
JACS 1981, 103, 5579Tetrahedron Lett. 1982, 2733
R1
NHR1
OHPh
H N
OPh
H
CH2O
Tetrahedron Lett. 1982, 2737
NH2R2R1 CHO
X
JACS, 1979, 101, 1310JACS, 1983, 105, 6622
CSA
Benzene, 80 oC, 24h (54-97 %) N
OR3
R1
R2
H
Synthesis of 3-Acyl-pyrrolidines
Cyanomethyl as a source for the iminium equivalent- Also functions as protection group
OH
N CN
Ph
AgNO3
EtOH, 1h rt. 60 % N
Ph
H
O
H
Tetrahedron Lett. 1982, 2741
Charge in rearrangement reactions
O
N N
O
Cope
Oxy-Cope Aza-Cope
rate acceleration up to1017
relative to Coperate acceleration up to1010
relative to Cope
Charged atom can distort the reaction pathway of concerted toward nonconcerted Rate acceleration due to delocalization in transition state
The aza-Cope-Mannich rearrangement - Directing the rearrangement by intramolecular trapping- Double bond incorporated in a suprafacial sense
NR1
R1
R2R3
H
Mannich
OHN
R1
R2R3
H
OHR3
NR2
R1
HOR3
NR2
R1
HOR3
[3,3]
Mannich
R1 = alkyl, phenyl, thiophene, pyridine; R2 = alkyl, benzyl; R3 = H, Me
R1 = H, Me; R2 = H, Me, n-C6H13; R3 = Ph
EtOH, reflux, (66-78 %)
- Cycloheptapyrrolidine moiety present in Gelsemine
R1 = H, CHPh2
Benzene, reflux, (66-78 %)
Acc. Chem. Res., 1992, 25, 352-359
ArAr
Larry E. OvermanRune Risgaard11-2-2013
Selected targets acheived with the Aza-Cope-Mannich reaction
OHN
HN
O
O
( )-Gelsimine26 steps, (1.4%)
Angew. Chem., 1999, 38, 2934
N
O
HN
HO2C
OH(-)-Actinophyllic acid 9 steps, (8%)
JACS, 2010, 132, 4894-4906
NH
CO2Me
N
MeO
H
dl-16-Methoxytabersonine 11 steps
JOC, 1983, 48, 2685
N
O
O
OH
H
(-)-Crinine10 steps, (6%)
Helv. Chim. Acta., 1985, 68, 745
NH
CO2Me
N
( )-Akuammicine10 steps, (8%)
JACS, 1993, 115, 3966
NH
N H
O
H
( )-Meloscine24 steps, (3%)
JACS, 1991, 113, 2598
Enantioselective total synthesis of (-)-Strychnine
OTIPS
OButMe3SnOH
AcO
7 steps
N
NN
O
I
1
1
2.5% Pd2dba322% Ph3As, LiCl
CO (50 psi)NMP 70 oC (80%)
OTIPS
OButO
R2N
1) t-BuO2H, Triton-B, THF2) Ph3P=CH2, THF
(84% 2 steps)
OTIPS
OBut
R2N
O
1) TBAF, THF, -15oC2) MsCl, Hünigs base, DCM, -23oC 3) NH2COCF3, NaH DMF, rt.
NHCOCF3
OBut
R2N
O
(83%)
HN
HO
NN
NO
OBut
(CH2O)n, Na2SO4
MeCN, 80 oC (98%)
N
ON
NN
O
OBut
NO
O
N
H H
H
(-)-Strychnine20 steps, (3% yield)
1) LDA, NCCO2Me, THF -78oC2) HCl in MeOH, reflux (70 %, 2 steps)
JACS, 1993, 115, 9293-9294
NCN
OH
O
OAgNO3
EtOH, rt (87%) N
O
H
Ar
BF3.OEt2
DCM, -20oC (97%)
OH
NHBn BnBn
1) HCHO, KCN2) Swern 3) t-BuLi, vinylbromide
N
O
Bn
H
H
OO
O
O
N
O1) HCl, Pd/C, H2, MeOH2) Formalin, Et3N, aq. 6N HCl
(65%, 2 steps)
7 steps
O
O
N
OH
OH( )pancracine7% overall yield (17 steps)
JOC. 1993, 58, 4662
Synthesis of ( )pancracine- Amaryllidaceae alkaloid
±
±
1) NaH, Benzene, 100oC2) KOH, EtOH:H2O, 60oC
(62%)
(1R, 4S) (39%)
N
NH OH
CO2Me
1) Zn, H2SO4, MeOH, reflux2) NaOMe, MeOH, rt.3) DIBAL, DCM, -78 oC
±
NH OH
O
N
H
H
H
CH2(CO2H)2, Ac2O, NaOAc, HOAc, 110oC
± ±
Larry E. OvermanRune Risgaard11-2-2013
OHR1
R2 R3
Synthesis of amines by rearrangement of allylic trichloroacetimidates(Overman rearrangement)Allylic imidate rearrangement discovered in 1937Works for 1o, 2o and 3o allylic alcoholsLarge enthalpic driving force (imidate to amide functionality 15 kcal/mol)Useful for synthesis of hindered aminesMild cleavage of the trichloroacetyl groupTrichloroacetimidates often used directly without purificationPreparation typically invole DBU in aprotic solvents or alkali metal hydridesEWG (CCl3 or CF3) results in more facile rearrangment compared to imidatesHigh stereoselection (preference for E isomer)
CCl3CNNaH
Et2O
OR1
R2 R3
CCl3
NH
[3,3]25-140 oC
Xylene
R1 R2R3
NHO
CCl3
HN O
CCl3
R3
HR1
R2
six-membered transition state for thermal rearrangement
Hg(II) and Pd(II) salts catalyze rearrangementMechanism proceeds through a iminomercuration-deoxymercurationCatalytic effect greater then 1012
HN O
R
CCl3
N O
R
CCl3
MX2
MX
HX
R
HN
CCl3
OMX2
JACS, 1976, 98, 2901-2910JACS, 1974, 96, 597
Conversion of allylic alcohols into a cis-vicinal diol- Conventional oxymercuration-demercuration gives trans-1,3-diol
OH
CCl3CHO
OO
HgX
CCl3H
HgX2 NaBH4
OO
CCl3H
Na, Et2O, rtOHOH
J.C.S. Chem. Comm., 1972, 1196
R = H. alkyl
Zn, AcOH, reflux(79 and 88%)
R = H, But;
R R R
R
R1 R2R3
NH2
Dilute NaOH(60-83% overall)
Catalytic asymmetric rearrangement of allylic trichloroacetimidates- Catalyzed by monomeric cobalt oxazoline palladacycles (COP)- >90% ee- COP-Cl superior in DCM but low solubility- COP-hfacac soluble in a wide variety of solvents. Higher solubility
HN O
CCl3
R
HN O
R
CCl3
NH2
R
Ph
Ph Ph
PhCo O
N
Pd
COP-Cl (1)
Ph
Ph Ph
PhCo O
N
PdOO
CF3F3C
COP-hfacac (2)
Cl
5 mol % COP38 C, 18 h.
(93%, 93% ee)
R = H, alkyl, aryl
JACS, 2003, 125, 12412-12413JOC, 2004, 69, 8101
Initial asymmetric Pd(II) catalyst developed - Only useful for N-arylbenzimidates- Coordination of the basic trichloroacetimidate nitrogen to the palladium center- Competing elimination reactions
Fe
SiMe3ON
t-BuPd
X2
JACS, 1999, 121, 2933-2934 (35-97% yield, 57-93% ee)
N O
Ar
R
N O
R
Ar
5 % catalystAr1 Ar1
NN Pd
Cl2
2+
(BF4)2-
JOC, 1997, 62, 1449-1456(25-68% yield, up to 60% ee)
DCM, rt
X = OCOCF3
Larry E. OvermanRune Risgaard11-2-2013
Prins pinacol rearrangement- Allylic acetals into highly substituted tetrahydrofurans- Catalyzed by lewis (EtAlCl2, BF3
.OEt2, SnCl4) (SnCl4 is generally superior) - Reaction occurs via chair topography with (E)-oxonium ion- Incoporation of doublebond in suprafacial sense- Both diastereoisomers gives the same product
JACS, 1991, 113, 5354-5365Acc. Chem. Res., 1992, 25, 352-359
O
O
H3C
CH3
CH3
CH3
R1
R2SnCl4
OH3C
O
H3CCH3
R2R1CH3
DCM, -78 - 0oC(73 and 90 %)
a) R1 = H, R2 = CH3; b) R1 = CH3, R2 = H
1a or b
O
R1
R2
OH
H3C
H
H3CCH3
CH3
Prins
O
HOH3C
H3C CH3
R1
R2Pinacol
OH3C
O
H3CCH3
R2R1
CH3
Mechanism:
O
OR1
R2
R3
OH
OR1
R2
R3
Cannot undergo C-C bond formation (5-endo-trig)
O
OHR1
R2
R3 Can undergo C-C bond formation (6-endo-trig)
CCl3
NHO
HRH2C
R1
Thermal rearrangement of propagylic trichloroacetimidates- Synthesis of trichloroacetamido-1,3.dienes- High stereoselectivity observed, (1Z,3E) isomer formed
R = H, alkyl,benzyl; R1 = H, alkyl, phenyl, TMS.
RH2C
H R1
HNO
CCl3
JACS, 1981, 103, 2809
[3,3] tautomerice
xylene, reflux (38-92%) R1
NO
CCl3H
HCH2
[1,5]
R
R1
HNO
CCl3
R
R
O
NH
CCl3 RO
O
R1R1COOH
JACS, 2005, 127, 2866-2867
Org Lett., 2007, 9, 911-913
R
O
NH
CCl3 RO
ArArOH
DCM, rt(60-100%, 87-99%ee)
1mol% COP-OAc
DCM, 38oC(45-88%, 80-98%ee)
1mol% COP-OAc
Catalytic asymmetric synthesis of chiral allylic esters and aryl ethers
JACS, 1987, 109, 4748
O
O
H3C
CH3
R1 SnCl4
OH3C
OH3C
R1
CH3
DCM, -78 to -23oC (60-77%) H
H
R = H, Me, PhR1 = Me, Et, i-Pr, CH2CH2Ph, CH=CH2, Ph, (E)-CH=CHPh
OH3C
H3C OH
MgBr
THF, rt(41-95%)
R
OH
OH
H3C
CH3R
CSAR1CHO
PhH, 80oC (64-70%)
AcO Pd CN
NH
O
Cl3C
R
NH Pd CN
O
Cl3C-OAc
R
NH Pd CN
O
Cl3C
R
O O
R1
Pd CN
ROCOR1
AcO HOAc
O
NH2Cl3C
R
OR1
O
RO
NHCl3C
Larry E. OvermanRune Risgaard11-2-2013
OTIPS
MeOMeO
CHOMeO
H
nn
mm
SnCl4
DCM, 0 oC 50-84%
m = 1, 2, 3; n = 1,2
- Oxocarbenium external to the ring formed upon Prins- Synthesis of attached rings with ring contraction
JOC, 2006, 71, 1581
OTIPS
MeOMeO
(87% ee)
CHOHMeO
CHOHMeO
(1.4 : 1.0)
(70% ee)
(CH2)n
OH
OH
- Ring-enlarging reactions (cis-fused octahydrobenzofurans and cycloheptatetrahydrofurans)- In most cases both cis and trans fused diols gives cis-fused rings
R1
RCHOn(H2C)
O
R/R1 = H, alkyl, aryl, vinyln = 0, 1, 2
O
(CH2)n
O
OHR1
R
R1
H
RSnCl4
DCM, 1h 50-94%
O
O
Me
RMe
X
- High enantiomeric purity obtained from nonracemic diols
(S)
X = NCO2Et, O, CH2; R = Me, Ph
SnCl4
MeNO2, -23 - 0oC 81-92%, >95% ee
OMe
O
MeR
X
JOC, 1987, 52, 3711JACS, 1991, 113, 5365
O
OH
R
R1
cis diols
OHO R
R1trans diols
OH
OH
OHCPh
O
HAcPh
BF3Et2O
DCM, -55oC (97%)
Hexahydroisobenzofuran synthesis- Alkene contained in ring- Synthesis of ladiellin, briarellin and asbestinin diterpenes
JACS, 2001, 123, 9033
Synthesis of oxacyclic ring systems
BrOH OH
OH
Ph O R
COMe
Ph
- Synthesis of trisubstituted tetrahydropyrans- Stereochemistry of sidechains evolves from single stereocenter- Found in polyether antibiotics, marine toxins and pheromones- DCM not suitable (trapping of carbocation with halide competitive)
JACS, 1999, 121, 1092-1093
1) t-BuLi2) CuCN
PhO
3)
85%
RCHO (2 eq.)SnCl4 or TfOH
MeNO2, -25oC (50-81%) 6-18:1
OR
R1
OH
H
Synthesis of carbocyclic ring systems
JOC, 2003, 68, 7143-7157R = CH2CH2Ph, Me, Bn, i-Pr, t-Bu, Ph, (E)-CH=CHPh
OH
OH
O
COMe
Ph
iPr-CHO (2 eq.) SnCl4
MeNO2, -25oC 68% (2R,4S,6R)
>99% eePh
SnCl4
MeNO2, 0 oC 50-84%
R
Larry E. OvermanRune Risgaard11-2-2013
OTMSR
CH(OMe)2
n DCM-78 to -23 oC (75-82%)
R = H, Me; n = 1, 2, 3
OR
H
OMe
JACS, 1989, 111, 1514
OR
H
OSnCl4 RuO4
55-72% overall
TMSO
H
n
OMeOMe
R = H, Me; n = 0, 1Tetrahedron, 2002, 58, 6473
1) SnCl4, DCM, -78 to -23 oC
2) RuO4, MeCN-H2O (65-72 %)
O
H
n
TESOR
HOSiMe3
- Allyl cation-initiated cyclization rearrangement to install 2-alkenyl substituent.- Protodesilylation occurs under reaction conditions with TMS
Tf2O
DCM, -78oC (54-80%)
R
H
O
n
n = 1, 2, 3; R = H, Me
>20:1
TESOR
O N
n
n = 0, 1, 2; R = H, Me
N
R
H
Tf2O, DTBMP
DCE, -20 (56-80%)
OTfO
n
R
H
O
n
OKHCO3 (aq)Et2O
JOC, 2002, 67, 6421
- Keteniminium ion initiated cyclization-pinacol rearrangements
JOC, 2002, 67, 6421
OTES
H
R1
R
OTES
HR1
n
n
n
n
OR
H
OR
Hn
OTES
R
OHMajor
MinorR1 = H, Me, TMS; ds = 1.5:1, 10:1, 20:1
SH
MeHO
Me RCHOBF3
.OEt2MgSO4
DCM, -20oC (51-71%)
R = CH2CH2Ph, Ar, (E)-CH=CHPh
SR
O
MeMe
Ph
SS
MeMeHO
- Synthesis of tetrahydrothiophenes- BF2
.OEt2 performs best
MeMe
OH
Major byproductJACS, 2000, 122, 8672
OTMS
CH(SPh)2
DMTSF
DCM, -45oC (80%)
H
H
SPh
O
JACS, 2001, 123,4851
Synthesis of hydrinans, hydroazulenes scaffolds containg functionalty in both rings
NDTBMP
- In cases where oxonium fails sulfonium can work as alternative
SS BF4
DMTSF
OTMS
CH(OMe)2
TMSOSnCl4
DCM
n n
OTMS
SPh
O
R1
R1
n
O
Larry E. OvermanRune Risgaard11-2-2013
Synthesis of (-)-citreoviral
SiMe2Ph
Me
OH
Me OTBDPS
Me
O
OTBDPS
MeMe
SiMe2Phi) TaCl5, Zn, PhH-DME
ii)
iii) aq. NaOHMe
1) TBAF, THF, rt2) TMSCl, imidazole, DCM, 0oC
OTMS
Me OTMS
MeSiMe2Ph
Me
Me
OMeMeOOTBDPS
TMSOTf DCM, -30oC
O
O
Me
Me
MeSiMe2Ph
Me
OTBDPSOMe Me
OTBDPS
MeO SiMe2Ph
(41%), >95% ee (47%)
SnCl4, DCM, -78oC, (89%)1) aq. HF, ACN2) p-TsOH, MeOH HC(OMe)3
O
PhMe2Si
OMeMe
MeMe Me
i) Li, NH3, THF-EtOHii) TBAF, THFiii) H2O2, KHCO3, MeOH O
O
HO
OMe
Me
MeMe Me(62%)
O
1) Bz2O, DMAP, pyridine 2) (CF3CO)2, urea-H2O2
DCM, 0oC then aq. NaHCO3
Me
HOMe OBz
MeOHO
O
OBz
MeMeO
Me TPAP, NMO
DCM, rt (81%)O
O
OBz
MeMeHO
Me DIBALH
hexane-DCM,-78oC (69%)
OMe
HOMe OBz
MeMe
CO2Et
(51%, dr = 4:1) Ph3P
Me
CO2Et
OMe
HOMe OH
MeMe
ODIBALH
hexane-THF 0oC to rt. (93%)
BaMnO4
PhH, 80oC (50%)
- 2,2-disubstituted 4-acyltetrahydrofurans containing different C2 substituents from unsymmetric ketone can be formed with high stereoselection- 4-acyl-3-(dimethylphenylsilyl)-tetrahydrofurans can serve as precusors of 4-acyl-3-hydroxytetrahydrofurans
Org. Lett., 2000, 2, 223
(-)-citreoviral (15 steps)
Me
NMe
O
OH
H
H
Magellanine25 steps (1.4%)
JACS., 1993, 115, 2992
OAcO
O
H
H
OAcH
(+)-Shahamin K20 steps (2.9%)
JACS., 2001, 20, 4851
O
OH
HH
H
OH
H
C7H15CO2
O
Briarellin F28 steps (0.7%)
JACS., 2003, 125, 6650
O
O
H
H
H H Br( )-kumausallene 13 steps (5.4%)
JACS., 1991, 113, 5378
O
O
O
N OH(+)-Sieboldine A 20 steps
JACS., 2010, 132, 7876
Selected targets acheived by Prins-Pinacol
±
(81%, 3 steps)
, THF
(72% + 20% Acetate)
PhH, reflux
OMe
HOMe OH
MeMe
OH
Larry E. OvermanRune Risgaard11-2-2013
Intramolecular asymmetric Heck reaction- Initial findings
J. Org. Chem., 1989, 54, 5846
O
OTf
CO2Me
I
Pd(OAc)2 (3 mol%)(R)-BINAP (9 mol%)Cyclohexene (6 mol%)
Ag2CO3 (2 eq.)NMP, 60oC
CO2Me
H
O
Et3N, Benzene, rt
74% (46% ee)
90% (45% ee)
- Synthesis of spirocycles with quatenary centers
General features- Two pathways proposed (Cationic and neutral)
ArOTfPd
PP
ArXPd
PP Pd
PP X
Ar
X = I, Br
PdPP
Ar
Cationic pathway
AgOTf
OTf
ArX
Neutral pathway
PdPP
AgX
PdPP X
ArPd
PP X
Ar PdPP
Ar
X
Reaction of arylhalides through neutral pathway often gives lower %eeSilver and Thallium salts (Ag2CO3, Ag2O, Ag3PO4, Tl2CO3, TlOAc) used to promote the cationic pathway. (JACS, 1998, 120, 6488)Common bases used (K2CO3, CaCO3, Et3N, i-Pr2NEt, PMP)Polar aprotic solvents are typically used (THF, ACN, DMF, DMA, NMP)Less basic silver salts (AgOAc, AgNO3) results in lower reaction rate and little asymmetric induction (JOC, 1992, 57, 4571)BINAP is by far the most widely used ligand.Depending on how HX is scavenged either enantiomer of the product can be formed using a single enantiomer of a chiral diphosphine.The order of reactivity X = I>OTf>Br>>ClCatalyst loading 5-10%. Most common used precatalysts Pd(OAc)2, Pd2(dba)3
JACS, 1998, 120, 6488
PR2
PR2
MeOMeO
PPh2
PPh2
(R)-(+)-BINAP R=Ph(R)-(+)-Tol-BINAP R=p-tolyl
(R)-MeO-BIPHEP
IN
O
R1
R2
Intramolecular Heck reactions of (Z)-a,b-unsaturated 2-iodoanilides- Synthesis of oxindoles
NO
R1R2
R1 = Me, Ph, t-Bu, CH2CH(OMe)2R2 = H, OTIPS, OTBDMS, OMe
DMA, 100 oC
(53-93%, 69-90% ee)
(JACS, 1998, 120, 6488)
XY
IO
O
X = N, O; Y = C=O, CH2
XY
O
O
Pd2(dba)3(R)-BINAPPMP or Ag3PO3
DMA or NMP, 100 oC
(55-75%, 41-96% ee)
Synthesis of oxindoles, indolines, dihydrobenzofurans- Depending on how HI is scavenged each enantiomer can be obtained (cationic vs neutral pathway)- Which HI acceptor is optimal for achieving highest %ee is substrate dependent
(JACS, 1998, 120, 6477)
O
OPPh2
PPh2
(R, R)-DIOP
PPh2
PPh2
(R, R)-CHIRAPHOS
Pd(OAc)2(R,R)-DIOP
PdPP
OTf
Ar
PdPP
Ar
Sol
X
PdP
ArXP
Pd2(dba)3(R)-BINAPPMP or Ag3PO3
Larry E. OvermanRune Risgaard11-2-2013
NH
O
Ar OMe
Synthesis of 3-alkyl-3-aryl oxindoles- A broad range of indole alkaloids contain a diarylsubstituted quatenary center
(48-91%; 71-98% ee)
JACS, 2003, 125, 6261
Triflates can be diverted to neutral pathway- Higher enantioselection without presence of silver salt- Identical low ee in presence of AgOTf- Addition of halide salts to the triflate enhanhced ee
Angew. Chem. 1997, 36, 518
XN
OTBDMSO
X = OTf or I
NO
OTBDMSPd(OAc)2(R)-BINAPhalide salt
DMF, 100 oC
Ar = Ph, 4-MeO-C6H4, 3-pyridyl, 4-AcNH-C6H4, 1-naphthyl, 2-NO2-C6H4,
N
OO
Bn
1) Methyl propagylic ether n-BuLi, -78 to -25 oC2) PhNTf2, -25 oC to rt
(59 %)
OTf
NH
O
OMe
Bu3SnHPd(PPh3)4
0 oC, (84 %)
OTf
NH
O
SnBu3
OMe
Pd2dba3P(2-furyl)3, CuIArI, NMP, rt(51-93 %)
OTf
NH
O
Ar
OMePd(OAc)2(R)-BINAPPMP
THF, 80 oC
NBn
NBoc
Compound( Addi+ve( Oxindole(yield(
%ee(
OTf$ %$ 72$ 43$
OTf$ nBu4NI" 62$ 90$
OTf$ nBu4NBr" 59$ 93$
OTf$ nBu4NCl" 52$ 93$
OTf$ nBu4NOTf" 70$ 42$
OTf$ PMPHI$ 40$ 91$
OTf$ PMPHBr$ 62$ 92$
OTf$ PMPHCl$ 60$ 88$
I$ %$ 76$ 91$
I$ PMPHI$ 62$ 91$
I$ PMPHBr$ 45$ 95$
I$ PMPHCl$ 75$ 94$
I$ AgOTf$ %$ 43$
NBoc
Synthesis of (+)-Minfiensine- Strychnos alkaloid
NH2
OTIPS
ON
O
TIPSON
TfO
CO2Me
1) p-TsOH, PhH, 50oC2) LHMDS, NCCO2Me, THF, -78oC3) NaHMDS, Comins' reagent
69 %, 3 steps
i) 9-BBN, , 0oC - rt.ii) NaOH, rt iii) PdCl2(dppf), THF, rt.
NHBoc
TIPSONCO2Me
BocHN
CsF,CsCO3, Comins' reagent
DMF, rt, 85 %TfONCO2Me
BocHN
71 %
10 %, Pd(OAc)2, ligand 1PMP, toluene, microwave 170 oC(75-87%, 99% ee)
NCO2Me
NHBoc
TFA, DCM
Ph2P N
O
t-Bu1
NMeO2C
75 %, 2 steps
NBoc
1) 9-BBN, THF, 100 oC, H2O2, NaOH2) TPAP, NMO, DCM
NMeO2C
63 %, 2 steps
1) TFA, DCM, rt2) K2CO3, ACN,
I
Br
NN
MeO2C I
OO
65 %, 2 steps
NN
MeO2C
O10 % PdCl2(dppf), K2CO3
MeOH, 70 oC, 74 %
NaHMDSComins' reagent
THF, -78oC, (86 %)
Larry E. OvermanRune Risgaard11-2-2013
NN
MeO2C
OTfPd(OAc)2, PPh3, Et3N
CO, MeOH, DMF (89%) NN
MeO2C
1) LiAlH4, THF, -78 oC2) NaOH, MeOH, H2O, 100 oC
NNH
OH
(+)-Minfiensine85 %, 2 steps
JACS, 2008, 130, 5368
HNN
HNO
O
HPh
HHN
NHHN
O
O
PhH
H
H
(+)-Asperazine 22 steps
Tetrahedron, 2007, 63, 8499
NHN
H
Quadrigemine C 19 steps (2% yield)
JACS, 2002, 124, 9008
HN N
H
NNH H
NNH H
OHN
HN
O
O
( )-Gelsemine26 steps (1,1% yield)
JACS, 2005, 127, 18054
N
O
OH
OH
(-)-Morphine (17 steps)
JACS, 1993, 115, 11028
NH
N
NO
O
OH
Angew. Chem., 2000, 39, 4596
(-)-Spirotryprostatin B (10 steps, 9% yield)
O
OMe
±
Vinylsilane terminated cyclization reactions- Hyperconjugation stabilizes beta carbonium ion- Carbon-silicon bond is strongly polarized (Electronegativity 2.35 vs. 1.64)- Electrophile directed to silicon bearing carbon- Complete regiocontrol of the double bond- Two mechanisms can be considered: Direct cyclization through beta silyl cation or via [3,3] aza-cope rearrangement.
NH
R R2 R1NR1 = TMSR2 = TMS R
R2endocyclicexocyclic
NR
R1
Synthesis of unsaturated azacycles (1,2,5,6-tetrahydropyridine)- Found in several alkaloids- A cyanomethyl amine can be used as formaldehyde equivalent.
TMSHN
RN
R = nC3H7, Ph, PMB
R1
R
R1 = H, nC6H13R1CHO
JACS, 1983, 105, 6994
ACN, reflux (68-92 %)
CSA
Vinylsilane-terminated cyclizations occur with preference for carbocation in sequence: tertitary trialkyl > secondary beta-silyl >tertiary alfa-silyl > secondary dialkyl > primary beta-silyl cations
Chemical Reviews, 1986, 86, 857
TMS
N MePhRR = H, CH2CN
NBn
Me
CH2O, p-TsOH or AgBF4
ACN
(33-69 %, 92-99 %ee)Tetrahedron Lett., 1993, 34, 5243
Preparation of enantioenriched tetrahydropyridines from silylpentenylamine
NO
O R
TMS
n
NO
1) NaBH4, MeOH2) TFA
(90-92%)
n R = H, Brn = 1,2
L-alanine
R
5 steps
NR
R1TMS N
R TMS
R2
Larry E. OvermanRune Risgaard11-2-2013
NH
H
MeSiMe3
NH
Me
HSiMe3
N
H
Me
N
Me
H
Synthesis of indoloquinolizidine ring system found in a variety of indole alkaloidsBoth (E) and (Z)-trisubstituted vinylsilanes can be cyclized with >98% retention
CSA, (CH2O)n
ACN, 80 oC (83 %)
(79 %)
JOC, 1982, 47, 5297( )-Deplancheine
Enantioselective totalsynthesis of Pumiliotoxin B and 251D- Pulimiotoxin B isolated from Panamanian poison frog Dendrobates pumilio in 1967 and pumiliotoxin 251 D from skin extracts of the Ecuadorian poison frog- Dendrabatid alkaloids- Poison used in blowdarts- Cardiotonic agent
NOH
CH3
H
R
H3CH
R =
CH3
OH
OH
CH3Pumiliotoxin B
R = n-Pr Pumiliotoxin 251 D
N COOBn
O
N
COOMeH
COOBn
1) 2 eq. MeMgI2) SOCl2, pyridine, THF3) m-CPBA, DCM
54 % 3 stepsH
N COOBn
OH
(2:1)
N COOBn
OHTMS
Me HCH2OBn N
O
O
H
SiMe3
CH2OBn
1) i-Bu2AlH, hexane2) MeLi, Et2O/hexane3)
L-proline
(+)-Streptazolin10 steps (4.2% yield)
NO
O
OH
H
JACS, 1987, 109, 6115-6118
N
OH
H
d,l-Epielwesine6 steps (30% yield)
Tett Lett., 1984, 25, 5739-5742
NO
O
H
SiMe3
CH2OBn
JACS, 1981, 103, 1851JACS, 1984, 106, 4192
1) KOH, EtOH, H2O, 90 oC2) Formalin, MeOH N
O
H
SiMe3
CH2OBn
CHO, CSA, ACN (60 %, 3 steps)
N
Me OH
MeH
CH2OBn
MeH MeH
1) Li/NH32) Swern ox.
(53 %, 2 steps)
N
Me OH
MeH
CHO
DCM, reflux (71 %)
O
OTBDPS
PPh3
N
Me OH
MeH
N
Me OH
MeH
O H
Me
OTBDPS
Me
OHHO
Pumiliotoxin B
NH
N
H CH3
H
H3CO2C OH (+)-Geissoschizine11 steps, (7.5% yield)
JACS, 1989, 111, 300-308
LiAlH4, THF, -20 oC - rt. (74 %)
±